1,3-disubstituted derivatives of oxazinan-2-ones are reportedly useful as inhibitors of 11-β-hydroxysteroid hydrogenase type 1 (“11-β-HSD1”) and for treatment of disorders associated 11β-HSD1 activity including, for example, diabetes mellitus (e.g., type II diabetes), obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica (see, e.g., WO/2009/134400).
The oxazinan-2-one 11-β-HSD1 inhibitors can be prepared, for example, by methods described in WO/2009/134400 and WO/2010/010150. In one method, a compound of formula (A) is allowed to react with an appropriate Grignard reagent RMgBr to provide the oxazinan-2-one 11-β-HSD1 inhibitor of formula (B) as depicted below:

However, the above method (and other known methods) present challenges for large-scale preparations. Additionally, compounds of formula (A) and formula (B) prepared by the known methods often contain a substantial amount of impurities (e.g., stereoisomers, structural isomers, and/or reagents). Thus, there is a need, for improved processes for making oxazinan-2-one 11-β-HSD1 inhibitors which are more amenable to large-scale production and provide a more pure form of the diastereomeric product.